Synthesis of Tripodal Bisphosphonate Derivatives Having an Adamantyl Basic Framework for Functionalizing Surfaces

Abstract

The present invention describes tripodal catechol derivatives with an adamantyl basic framework for the functionalisation of surfaces, and methods for their production and use. A fourth remaining position of the adamantane skeleton is suitable to be optionally functionalised by so-called click reactions, for example with biomolecules, polyethylene glycol or active agents. The compounds according to the present invention have the general formula X-Ad{(CH 2 ) n —Y—C[PO(OH) 2 ] 2 R 1 } 3 , wherein Ad stands for the adamantyl skeleton, X for a group —(CH 2 ) p —R 3 , wherein p=0 to 10 and R 3 is selected from —H, —NH 2 , —NO 2 , —OH, —SH, —O—NH 2 , —NH—NH 2 , —N═C═S—, —N═C═O—, —CH═CH 2 , —C≡CH, —COOH, —(C═O)H, —(C═O)R 4 Y stands for —CH 2 —, —CH═CH—, —C≡C—, —O—, —S—, —S—S—, —NH—, —O—NH—, —NH—O—, —HC═N—O—, —O—N═CH—, —NR 2 —, -aryl-, -heteroaryl-, —(C═O)—, —O—(C═O)—, —(C═O)—O—, —NH—(C═O)—, —(C═O)—NH—, —NR 2 —(C═O)—, —(C═O)—NR 2 —, —NH—(C═O)—NH—, —NH—(C═S)—NH—, R 1 represents a hydrogen atom or a hydroxy group, R 2 stands for a linear or branched alkyl group and R 4 for a linear or branched alkyl group or an aryl group. The production of the compounds occurs by reacting a compound X-Ad[(CH 2 ) n —Y′] 3 with a reagent Y″C[PO(OH) 2 ] 2 R 1 to the corresponding compound X-Ad{(CH 2 ) n —Y—C[PO(OH) 2 ] 2 R 1 } 3 and subsequent purification of the reaction product. Y′ and Y″ are hereby precursors of Y. The compounds according to formula (I) according to the present invention are suitable to be used in a method to functionalise surfaces. The X group of the compounds according to the present invention is suitable to be optionally coupled to an effector, for example, by means of click chemistry.

1 . A compound according to formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 n and m each, independently, is an integer between 0 and 10, 
 R 1  is a hydrogen atom or a hydroxy group, 
 Y is a bond, —CH 2 —, —CH═CH—, —C═C—, —O—, —S—, —S—S—, —NH—, —O—NH—, —NH—O—, —HC═N—O—, —O—N═CH—, —NR 2 —, -aryl-, -heteroaryl-, —(C═O)—, —O—(C═O)—, —(C═O)—O—, —NH—(C═O)—, —(C═O)—NH—, —NR 2 —(C═O)—, —(C═O)—NR 2 —, —NH—(C═O)—NH—, or —NH—(C═S)—NH—, 
 R 2  is a linear alkyl group with 1 to 10 C atoms or a branched or cyclic alkyl group with 3 to 10 C atoms, 
 X is —(CH 2 ) p —R 3 ; a branched alkyl, alkenyl or alkynyl group with 3 to 10 C atoms; a cyclic alkyl, alkenyl or alkynyl group with 3 to 10 C atoms; or an aryl or heteroaryl group, 
 p is an integer between 0 and 10 
 R 3  is —H, —NH 2 , —NO 2 , —OH, —SH, —O—NH 2 , —NH—NH 2 , —N═C═S—, —N═C═O—, —CH═CH 2 , —C≡CH, —COOH, —(C═O)H, or —(C═O)R 4  wherein the hydroxy, thio, amino or C═O groups are optionally suitable to be protected by a protective group, —N 3 , —OR 4 , —COOR 4 , —NR 4 R 5 , —CO—NHR 4 , —CONR 4 R 5 , —NH—CO—R 4 , or 4-(2,5-dioxopyrrol-1-yl), and 
 R 4  and R 5  each, independently, is a linear alkyl group with 1 to 10 C atoms, a linear alkenyl or alkynyl group with 2 to 10 C atoms, a branched alkyl, alkenyl or alkynyl group with 3 to 10 C atoms, or a cyclic alkyl or alkenyl group with 3 to 10 C atoms, 
 
       wherein, if X is a branched alkyl, alkenyl and alkynyl group, a cyclic alkyl or alkenyl group, an aryl or heteroaryl group, then one C atom of this group X is optionally substituted with R 3 . 
     
     
         2 . The compound according to  claim 1 , wherein Y is a bond, —CH 2 —, —NH—(C═O)—, —(C═O)—NH—, or —NR 1 . 
     
     
         3 . The compound according to  claim 1 , wherein n is an integer between 0 and 3. 
     
     
         4 . The compound according to  claim 1 , wherein m is an integer between 0 and 3. 
     
     
         5 . The compound according to  claim 1 , wherein X is —(CH 2 ) p —R 3 , and p is an integer between 0 and 3. 
     
     
         6 . The compound according to  claim 1 , wherein
 X is —(CH 2 ) p —R 3 ,   R 3  is —H, —OH, —NH 2 , —NO 2 , —NH—NH 2 , —NR 4 R 5 , —O—NH 2 , —NH—(C═O)—C≡CH, —C≡CH, —N═C═S, —N═C═O, —COOH, —(C═O)H, or —(C═O)R 4 , and   p is an integer between 0 and 3.   
     
     
         7 . A method for the production of a compound according to  claim 1 , the method comprising:
 reacting a compound X-Ad[(CH 2 ) n —Y′] 3  with a reagent Y″C[PO(OH) 2 ] 2 R 1  to produce X-Ad{(CH 2 ) n —Y—C[PO(OH) 2 ] 2 R 1 } 3  as a reaction product, and   purifying the reaction product,   
       wherein Ad is the adamantly skeleton, and Y′ and Y″ are precursors of Y. 
     
     
         8 . The method according to  claim 7 , wherein X is a hydrogen atom. 
     
     
         9 . The method according to  claim 7 , wherein
 X is —(CH 2 ) p —R 3 ,   R 3  is selected from —OH, —NH 2 , —NO 2 , —NH—NH 2 , —NR 4 R 5 , —O—N H 2 , —NH—(C═O)—C≡CH, —C≡CH, —N═C═S, —N═C═O, —COOH, —(C═O)H, or —(C═O)R 4 , and   p is an integer between 0 and 3.   
     
     
         10 . The method according to  claim 9 , wherein R 3  is protected by a protective group (Pg) prior to reacting the compound with the reagent Y″C[PO(OH) 2 ] 2 R 1 , so that the compound Pg-X-Ad[(CH 2 ) n —Y′] 3  is reacted with the reagent to produce a corresponding compound Pg-X-Ad{(CH 2 ) n —Y—C[PO(OH) 2 ] 2 R 1 } 3 . 
     
     
         11 . (canceled) 
     
     
         12 . (canceled) 
     
     
         13 . (canceled)